The JPL called this ephemeris is a "significant advance" over predecessors like DE405 / DE406 and cited accuracies that are in many cases ten times greater, such as giving the position of Venus within 200m and the positions of Earth and Mars within 300m over the last decade. Note that even greater accuracies are achieved, for Mercury and Venus in particular (but not for the Moon), by DE423 which also has the advantage of covering a 400-year period instead of only 150 years.

Greater accuracy can also be expected from the long-term ephemeris DE422 since it incorporates more spacecraft observations than DE421. It also covers a period of 6000 years, making it useful to astronomy historians. But as it requires a half-gigabyte of disk space, some users may prefer DE421.